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  • 1
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    Outcome of patients with Myelofibrosis relapsing after allogeneic stem cell transplant: a retrospective study by the Chronic Malignancies Working Party of EBMT
    Wiley ; 2018
    In:  British Journal of Haematology Vol. 182, No. 3 ( 2018-08), p. 418-422
    Details
    In: British Journal of Haematology, Wiley, Vol. 182, No. 3 ( 2018-08), p. 418-422
    Abstract: Allogeneic Haematopoietic Stem Cell Transplant (allo‐ HSCT ) remains the only curative approach for Myelofibrosis ( MF ). Scarce information exists in the literature on the outcome and, indeed, management of those MF patients who relapse following transplant. We hereby report on the management and outcome of 202 patients who relapsed post allo‐ HSCT for MF .
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.2018.182.issue-3
    DOI: 10.1111/bjh.15407
    RVK:
    XA 34100
    Language: English
    Publisher: Wiley
    Publication Date: 2018
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  • 2
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    Prognostic Significance of Complement System Activation After Allogeneic Hematopoietic Stem Cell Transplantation.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1166-1166
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1166-1166
    Abstract: Abstract 1166 Poster Board I-188 Introduction: The complement system consists of several serum proteins and cell membrane receptors that can be activated by three possible pathways leading to the production of pro-inflammatory factors such as the anaphylatoxins C3a and C5a and the formation of the membrane attack complex. The complement system has been implicated in the pathophysiology of several immune diseases and we previously reported that it was activated after allogeneic haematopoietic stem cell transplantation (HSCT) both in humans and mice. It's activation after allogeneic HSCT following a myeloablative conditioning could predict the development of gastrointestinal (GI) GVHD in humans. We now present updated data with long term follow up on an enlarged series of patients who did or did not activate complement after allogeneic HSCT. We also discuss the preliminary results of the inhibition of complement activation on experimental models of GVHD. Materials and methods: Complement activation was determined by measurment of complement proteins before and once a week up to 3 months after allogeneic HSCT in 34 patients allografted for diverse haematological malignancies in our institution following conventional myeloablative conditioning. Results were correlated to the clinical evolution of allogeneic HSCT. Preclinically, inhibition of mouse complement activation by C1 inhibitor esterase or an anti-C5 monoclonal antibody was tested in a parent (C57BL/6, H-2b) to F1 [(C57BL/6xDBA2), H-bd] GVHD mouse model. Lethally irradiated (9.75 to 11 Gy) mice reconstituted with either syngeneic or allogeneic bone marrow cells and splenocytes (107 and 13 to 20 ×106 cells/recipient, respectively) were treated with complement inhibitors between day-7 to Day 21 or day 1 to Day 28 post-HSCT. Clinical Results: Fifteen (44%) patients showed an activation of the classical pathway, as defined by a decrease of C3 and C4 proteins below normal values and of at least 50% of their pre-HSCT levels. Activation occurred during the 4 first weeks following HSCT in 11 patients, between 6 and 8 weeks in 2 cases and later, after withdrawal of immunosuppression, in 2 patients. Pre-transplant characteristics (age at transplant, sex, underlying haematological disease, conditioning regimen, use of ATG, type of donor and CMV risk) of patients who showed an activation of complement were comparable to those who did not. We confirmed that activation of complement was significantly associated with acute GI GVHD (80 % in the activated group versus 5.3% in the non activated, p=0.0028) and occurred from 1 to 3 weeks before the appearance of clinical GVHD. Patients in the activated group had a significantly increased incidence of capillary leak syndrome concomitant to the conditioning toxicity or GVHD (66.7% in the activated group vs 10.5% in the non activated, p=0.019). There was no significant difference between the groups in terms of skin or hepatic acute GVHD, TMA, VOD and chronic GVHD. In a landmark analysis by day 100 post-HSCT, overall survival was significantly impaired in the group of patients with complement activation (p=0.008) because of increased toxicity related mortality (p=0.02) and relapse (p=0.01) risks in comparison to the patients without complement activation. Preclinical Results: Complement inhibitors capable of blocking the first pathway (C1 inhibitor esterase) or terminal complement activation (anti-C5 mAb) were used in a mouse model of GVHD. These inhibitors were administrated before and/or during the phase of activation of complement which starts on day 4 post-HSCT. However, GVHD clinical signs and mortality did not appear to be improved following complement inhibitor administration in this mouse model. Conclusion: Activation of complement after allogeneic HSCT following a myeloablative conditioning appears as a predictive marker of acute GI GVHD and a pejorative prognostic factor of transplant outcome. However, inhibition of complement activation in a mouse experimental model of allogeneic HSCT did not allow the control of GVHD. It is not clear, therefore, that this mouse model is useful as a model of human GVHD. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1166.1166
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 3
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    Ruxolitinib For Patients With Primary Or Secondary Myelofibrosis before Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT): A Retrospective Study Of The Société Française De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC)
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 2111-2111
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2111-2111
    Abstract: Up to now allo-HSCT is the only curative treatment for patients with myelofibrosis (MF) (Ballen, et al, Guardiola, et al 1999, Kroger, et al 2007, Robin, et al 2011). The engraftment rate ranges from 70% to 95% and is influenced by spleen size (delayed in patients with splenomegaly and faster in patients splenectomized prior to allo-HSCT). JAK1/JAK2 inhibitor Ruxolitinib is reported to decrease spleen size and constitutional symptoms. These effects could also be benefit for patients eligible for transplantation, by reducing their splenomegaly and improving their performance status, factors known to impact the results of allo-HSCT. The present study analyzes outcome of patients with MF who have been reported to the SFGM-TC registry. From 2008 to 2013, 11 patients with primary MF (n=7), MF secondary to PV or ET (n=3) or acute myeloid leukemia secondary to MF (n=1) were treated with Ruxolitinib before allo-HSCT. Median age at allo-HSCT was 54 years (range: 44-66); there were 9 men and 2 women. Nine patients had the JAK2V617F mutation. At Ruxolitinib initiation, median white blood cells were 4.4G/L (3.5–13.7), hemoglobin was 10g/dL (7.5-13.3) and platelets were 99G/L (41-290); all patients had palpable splenomegaly and 8 had constitutional symptoms. Lille score was low in 4, intermediate in 2 and high in 4 patients, respectively. Cytogenetics were favorable in 2, unfavorable in 3 (complex karyotype) and not done or failure in 6 patients, respectively. The median time between diagnosis and treatment with Ruxolitinib was 353 days (16-2687) and median time from diagnosis to allo-HSCT was 433 days (199–2793). Ruxolitinib was progressively tapered in 3 patients (with steroids for 2 of them) and discontinued without tapering in 4 (missing data for 3). Median time between Ruxolitinib withdrawal and allo-HSCT was 10.5 days (4-66). All patients received reduced intensity conditioning regimen based on Fludarabine and a graft-versus-host disease (GVHD) prophylaxis including ciclosporine. Donors were: HLA matched sibling in 4, matched unrelated donor in 3 and mismatched unrelated donor in 4 patients. All but one patients received peripheral stem cell transplantation (one patients received bone marrow). Before allo-HSCT, 7 patients were in partial response and 4 were stable. After Ruxolitinib treatment, 8 patients had an estimated reduction of spleen size 〉 25% and 2 underwent splenectomy. There was no progressive disease on therapy and only one patient experienced a grade III-IV hematological toxicity. All patients had neutrophil engraftment ( 〉 0.5G/L) in median on day +17 and 10/11 patients had platelet engraftment ( 〉 20G/L) in median on day +21. Chimerism was full donor in 8, mixed in 1 (who relapsed at day 178), and not available in 2 patients, respectively. One patient who was 100% donor chimerism remains pancytopenic and transfused 90 days after allo-HSCT. Three patients experienced grade II and 2 grade IV acute GVHD after a median time of 18 days after allo-HSCT. Acute GVHD was refractory to corticosteroids in 2 patients and was the cause of death in 1 patient. Only 2 patients had chronic GVHD. Median time from Ruxolitinib initiation to last follow-up was 339 days (166 – 1928), 6 (54%) patients were assumed in complete remission (blood cell count normal and 100% donor chimerism) and 9 (80%) were alive. Two patients relapsed on days 77 and 148 and one of them received a second allo-HSCT. In this retrospective study, Ruxolitinib before allo-HSCT seems to be well tolerated with excellent engraftment rate. A prospective study (JAK-ALLO) is ongoing in France on behalf of SFGM-TC to precisely analyze the role of Ruxolitinib before allo-HSCT. Disclosures: Kiladjian: Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity’s Board of Directors or advisory committees. Mohty:Novartis: Honoraria, Research Support Other. Robin:Novartis: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.2111.2111
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 4
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    Treatment of Relapse After Allogeneic Hematopoietic Stem-Cell Transplantation for Myelodysplastic Syndrome: A Large-Scale Study On Behalf of the Société Française De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC)
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 593-593
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 593-593
    Abstract: Abstract 593 Background: Treatment of patients with myelodysplastic syndrome (MDS) relapsing after allo-SCT remains disappointing and prognostic factors for outcome are still unclear. Several therapeutic approaches are offered to those patients including: palliative and supportive care, intensive chemotherapy (ICT), demethylating agents (DMA) and immunotherapy with either donor lymphocyte infusion (DLI) or second allo-SCT. The aim of this study was to identify predictive factors for outcome and to investigate the impact of different treatment groups on survival. Methods: We report a retrospective study on 137 consecutive MDS patients who relapsed after allo-SCT between Jul 1999 and March 2011 in 19 French and Belgian centers. Data quality was ensured using computerized discrepancy errors and vigorous on-site data verification of every single file. HLA matching was double-checked by the French Bone Marrow Donor Registry. Results: At diagnosis, 61 patients presented RA/RARS/RCMD, 27 RAEB1 and 49 RAEB2 according the WHO classification. Cytogenetic was unfavorable in 47 patients (35%) while 76 patients (57%) had IPSS Int-2 or High and 52 (39%) had progressed to a more advanced disease before allo-SCT. At transplant, 62 patients (47%) were considered responders (in CR or PR), while 70 were transplanted with progressive disease (untreated, stable without hematological improvement, relapsed or refractory disease). Patients received either myeloablative (MAC) (n=38) or nonmyeloablative (RIC) (n=99) conditioning. Source of stem cells was BM (n=40) or PBSC (n=97) from sibling (n=89) or allele well-matched unrelated (10/10) (n=48) donors. Median age at relapse was 57 years (range, 19–70). Patients aged 〈 18 years and those who received graft from either cord blood or mismatched donor were excluded. Post-transplant relapse occurred after a median time of 6 months (range, 0.8–102). Of the 109 evaluable patients 62 (57%) had 〉 = 10% of marrow blasts, of whom 38 had 〉 = 20%. At the time of relapse, 61 patients were still under immunosuppressive treatment which was quickly stopped in all of them. For the analysis, patients were divided into three groups according to ultimate salvage received treatment as follows: palliative and supportive care (PSC-group) (n=42, 31%), cytoreductive treatment alone (CRT-group) [DMA (n=18, 13%) and ICT (n= 11, 8%)] and immunotherapy preceded or not by a CRT (IT-group) [DLI (n=48, 35%) and second allo-SCT (n=18, 13%)] . With a median follow-up of 33 months from the relapse, estimated 2-year overall survival was 2.4%, 6.7% and 30.3% for the PSC-group, CRT-group and IT-group, respectively (p 〈 .0001). In multivariate analysis, 3 independent factors have been identified: the absence of immunotherapy HR= 1.45 [95% IC= 1.25–1.69, p 〈 .0001], early relapse within 6 months after transplant, HR=2.71 [95% IC= 1.66–4.45, p 〈 .0001] and marrow blasts at relapse 〉 = 10%, HR=2.56 [95% IC= 1.55–4.22, p 〈 .0001]. Conclusion: This study shows that salvage immunotherapy (DLI or second allo-SCT) provides the best results and should, whenever possible, be offered to patients with MDS who relapse after allo-SCT especially those with low tumor burden. Patients who received cytoreductive treatment alone (be it chemotherapy or DMA) had less satisfactory outcome. Our results emphasize the need to perform prospective protocols combining cytoreductive treatments and immunotherapy. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.593.593
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 5
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    Hematopoietic Multipotent Progenitor Cells Mobilized by G-CSF Can Inhibit Gvhd
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 2969-2969
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2969-2969
    Abstract: Abstract 2969 Backgound. Acute graft-versus-host-disease (aGVHD) is a frequent life threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Despite the infusion of higher doses of T cells with the use of G-CSF-mobilized HSC grafts, the incidence of aGVHD is not increased. The mechanisms by which G-CSF-mobilized HSC can control GVHD are imperfectly elucidated. We previously described the mobilization of murin hematopoïetic progenitor cells (HPCs) by G-CSF and FLT3 ligand capable of inducing tolerance against autoimmune diabetes in the nude mice (Kared, Immunity 2006). We now show that G-CSF can mobilize murin HPCs with immunoregulatory functions in the allogeneic immune response and describe their mechanisms of action. Methods. Mobilization of HPCs is performed by subcutaneous administration of human recombinant G-CSF at 200μg/kg per day, for 4 consecutive days in the C57BL6 (H-2b) mouse. HPCs are collected in the spleen by FACS sorting according to their phenotype: Lin- Sca1high cKithigh FLT3low CD34+ CD106+ CD127−. In vitro, functions and mechanisms of action were analyzed by co-cultures with i) T cells (from C57BL6) activated by anti-CD28 and -CD3 mAbs or activated by BALB/c (H-2d) allogeneic splenic LPS matured dendritic cells, ii) C57BL6 splenic selected CD4+CD25high T regulatory T cells activated by anti-CD28 and -CD3 mAbs iii) activated antitumor specific CD8 T cells (C57BL6 ovalbumin specific TCR transgenic T cells). These different cultures were performed in the presence or absence of inhibitors of selective cytokines or other regulatory molecules. In vivo, we assessed the effect of donor HPCs on GVHD development by injecting C57BL6 derived HPCs (0.5×106/mouse), splenic T cells (1×106/mouse) and T depleted bone marrow cells (5×106/mouse) into lethally irradiated (8 Gy) Balb/c recipients. Results. In vitro, as compared to controls without HPCs, after 3 days of culture, HPCs: 1) promote the proliferation of natural T regs activated by anti-CD3 and anti-CD28 ( 〉 80% at 3 days of culture compared to control 〈 50%), 2) inhibit the proliferation of activated T cells ( 〉 80% T cells blocked before 4 divisions as compared to control-T cells alone 〉 80% after 4 divisions- p 〈 0, 001) and 3) induce the apoptosis of activated T cells (30% increased, p=0, 01). The proliferation of T regs was cell contact dependant and required the presence of TGF-b. The inhibition of T cell activation required IFN γ produced by activated T-cells and some contact-dependent stimuli. In such pro-inflammatory conditions, HPCs differentiate after 4 days in myeloid derived suppressor cells (MDSC). These cells could then produce NO in response to IFN γ and suppress the proliferation of activated T cell. However, T cell suppression was not dependant on L-arginine depletion. Induction of apoptosis of T cells was Fas/Fas-L dependant. Although in the presence of HPCs the proliferation of CD8+ T TCR transgenic against the dominant ovalbumin epitope SIINFEKL was reduced, the cytotoxic response against the SIINFEKL-pulsed EL4 cell line was enhanced (cytotoxicity 〉 90% with HPCs versus 〈 90% w/o HPCs, p 〈 0, 001). In addition, HPCs express CCR7 and CD62L, which should allow their migration to the sites of allopriming. In vivo, none of the mice that had received allogeneic HSCT with HPCs developed clinical or histological GVHD signs as compared to 50% of the control allografted mice without HPCs. Conclusion. Hematopoietic progenitor cells acquire an immunosuppressive potential after G-CSF mobilization. These cells can be isolated from mobilized peripheral stem cells and suppress GVHD while possibly preserving the GVL effect. Work is underway in humans to identify and amplify this population ex vivo for potential therapeutic application in allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.2969.2969
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 6
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    Complement System Activation after Allogeneic Bone Marrow Transplantation May Early Predict the Development of Acute Gastrointestinal GVHD.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 2186-2186
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2186-2186
    Abstract: The Complement system consists of several serum proteins and receptors that belong to the innate immune response. It is activated by three possible pathways leading to the production of pro-inflammatory factors and the formation of the membrane attack complex. As it is known to be implicated in the physiopathology of several immune-mediated diseases, we investigated its role in GVHD in both humans and a mouse model. Thirty nine patients allografted for diverse haematological malignancies in our institution following myeloablative conditioning (n=22) or reduced intensity conditioning (RIC) (n=17) entered prospectively the study. Extensive exploration of the Complement system was carried out before and sequentially after allogeneic haematopoietic stem cell transplantation (HSCT). An activation of the classical pathway, as defined by a decrease of C3 and C4 proteins below normal values and of at least 50% of their pre-HSCT levels, was observed in 10/39 patients. Such activation was found in 9/22 (40%) patients who received myeloablative conditioning and in 1/17 (5.8%) patients allografted with RIC. This phenomenon occurred during the 4 first weeks after HSCT in 7 patients, at two months in one case and after withdrawal of immunosuppression in 2 patients. We observed a strong association between Complement activation and the development of acute gastrointestinal (GI) GVHD. Nine of the 10 patients who activated the Complement system (90%) developed GI GVHD within two weeks following the activation. By contrast only 4 of the 29 who did not activate the system, all of whom had received a RIC, developed GI GVHD (13.8%) (p & lt;0.001). No correlation was found with the use of monoclonal antibodies, the degree of HLA and sex disparity between donor and recipient or the CMV status before the graft. We then analyzed Complement activation in a parent (C57BL/6, H–2b) to F1 [(C57BL/6×DBA2), H–bd] GVHD mouse model. Serum C3 Complement fraction and serum albumin protein (SAP) were measured sequentially after HSCT in lethally irradiated (9.75 Gy) mice reconstituted with either syngeneic or allogeneic bone marrow cells and splenocytes (107 and 13×106 cells/recipient, respectively). In comparison to naïve non HSCT recipient mice, the C3/SAP ratio was increased up to three times from Day 4 to 28 in syngeneic HSCT recipients (p=0.0002), reflecting the inflammatory response induced by the conditioning regimen without Complement activation in this conditioned non-GVHD control group. By contrast, the C3/SAP ratio was significantly decreased from Day 7 to 28 after HSCT in allogeneic recipients of HSCT in comparison to that of naïve (p=0.0005) and of syngeneic recipients (p=0.0002), indicating an activation of the Complement system in allografted mice that uniformly developed GI GVHD by Day 20 after HSCT. In conclusion, our results show that allogeneic HSCT induces Complement activation in both humans and mice, as a consequence of the immune alloresponse and not as a direct effect of the conditioning regimen. They also suggest that Complement C3 and C4 dosage might be useful in early prediction of acute gastrointestinal GVHD in humans. Ongoing studies are investigating the potential protective effect of pharmacological inhibitors of Complement activation on the development of GVHD in our mouse model.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.2186.2186
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 7
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    Tacrolimus Given As an Alternative to Cyclosporin after Allogeneic HSCT in Case of Renal Impairment: A Prospective Pilot Study
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 5749-5749
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5749-5749
    Abstract: Introduction Tacrolimus is a widely used calcineurin inhibitor in solid organ transplantation and in allogeneic HCST for prophylaxis and treatment of GvHD. Recently, several transplantation centers showed advantageous effects for patients with tacrolimus in comparison with cyclosporin A (CsA) regarding renal function after renal and heart transplantation. Based on these observations, we have conducted a prospective study in wich CsA is switched for tacrolimus (Prograf or Advagraf ER) in case of renal impairment due to CsA after allogeneic HSCT. Patients, Method We enrolled 31 consecutive patients between March 2012 and March 2016 from two centers in France (Lyon and Nancy) with renal impairment due to CsA (serum creatinine 〉 90 µMol/L), the conversion dose was established on an mg:mg basis 1 :100 from CsA total daily dose to a total daily dose of tacrolimus. In this cohort, 27 patients received oral formulation Advagraf and 4 received Prograf initially i.v. and then converted to oral form. The dose was readjusted to obtain a tacrolimus blood trough level between 5 and 15 µg/L.We evaluated the tacrolimus blood trough level changes after conversion, serum creatinine, potassium, one time a week from one week after switching to discontinuation. Before the switch, 22 patients (70%) had CsA for GvHD prophylaxis and 9 patients (30%) for acute GvHD treatment in association with prednisone. Results All patients had hematological malignancies, the median age was 54 years (range, 17-67). Twelve patients (39%) had a matched related donor, 19 patients (61%) had a HLA-10/10 matched unrelated donor .The stem cell source was bone marrow for 11 patients (35.5%), PBSC for 18 patients (58%) and cord blood for 2 patients (6.5%). Fifteen patients (48%) received a myeloablative regimen and 16 patients (52%) a reduced intensity regimen. ATG was administrated in 28 patients and 10 patients received 12Gy TBI. The status at transplantation was CR1 for 13 patients (42%), CR2 or more for 10 patients (32%), partial response for 5 patients (16%) and 3 patients (10%) had a refractory leukemia. The median follow-up after transplantation was 35.6 months (range, 1-51,7). The median time of switch for tacrolimus was 40 days (range, 3-1286) and the median of serum creatinine in wich the switch was realized was 110 mol/L (range, 94-262). Concerning creatinine level, the median of serum creatinine was 105 µmol/L (range, 51-262) with CsA and 84 µmol/L (range, 50-129) with tacrolimus (p 〈 0.01) (Figure 1). Moreover the median of potassium level was 4.2 mmol/L (range,3.2-5.2 ) with CsA and 4.0 (range,3-5.1 ) with tacrolimus (p 〈 0.001 ) (Figure 2). Before the switch, the median of serum creatinine was 94µMol/L (range, 51-213),106µMol/L (range, 57-262) and 110 µMol/L (range, 75-180) at D+30, D+45 and D+60 respectively after transplantation for patients with CsA and the median residual value of CsA was 250 µg/l (range, 162-629) at D+30. The median dose of CsA was 200mg (range, 25-600) and the median dose of tacrolimus was 2.4mg (range, 0.5-5). The median of serum creatinine was 88µMol/L (range, 59-130), 84µMol/L (range,54-129) and 84µMol/L (range, 54-129) at D+5, D+15 and D+30 after the switch for tacrolimus and the median residual value of tacrolimus was 8.7µg/l (range,2.7-15) at D+20 after the switch (Figure 3). The cumulative incidence of grade II-IV aGvHD was 53% (95%CI, 25-64) at +90 days. Seventeen patients (58%) developed aGvHD grade ≥ II and 7 patients (22%) developed chronic GvHD with NIH score 2-3 after discontinuation of GvHD prophylaxis. The cumulative incidence of cGvHD was 26.5% (95%CI, 7.75-45) at 1 year, 32.14%(95% CI, 11.6-52) after 2 years and 32.14% (95% CI, 11.6-52) after 3 years. In this cohort, 27 patients (87%) are alive and 26 patients (84%) are in complete response at this time. Four patients died two from relapse, one from cerebral bleeding and one from severe pneumonia (fungal and Pneumocystis carinii infection). Conclusion The conversion from CsA to Tacrolimus was followed by a clinically significant improvement in kidney function with stable tacrolimus blood trough levels. Based on these observations, we suggested that the use of tacrolimus in case of renal impairment due to CsA is safe in allogeneic HSCT patients. Disclosures Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.5749.5749
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 8
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    Impact of Azacitidine (AZA) Prior to Allogeneic Stem Cell Transplantation (allo-SCT) for Myelodysplastic Syndromes (MDS): A Large-Scale Study on Behalf of the SFGM-TC and GFM Groups
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 160-160
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 160-160
    Abstract: Abstract 160 Background: Until the early 2000s, treatment prior to transplant in candidates to allo-ST varied according to cytogenetic score and percentage of BM blasts, from best supportive care (BSC) to AML-type chemotherapy (intensive CT). Recently AZA has become a reference treatment of IPSS higher risk MDS not candidates for allo-SCT, but its role prior to transplant in order to reduce the tumor burden remains uncertain. Methods: We report a retrospective study on 470 consecutive MDS patients who underwent allo-SCT between Jan 1999 and Dec 2009 in 26 French and Belgian centers. Inclusion criteria were: age 〉 18 and allo-CST from either sibling (n=285) or HLA-A, -B, -C, -DRB1 and -DQB1 allele matched unrelated donor (10/10) (n=172) for MDS or AML/RAEB-t (with 20–30% BM blasts). Data quality was ensured using computerized discrepancy errors and vigorous on-site data verification of every single file. HLA matching was double-checked by the French Bone Marrow Donor Registry. Results: The first 405 files analyzed until now are presented, including 250 males and 155 females. At diagnosis, WHO was: 102 RA/RARS/RCMD, 136 RAEB-1, 146 RAEB-2 and 18 RAEB-t/AML; Cytogenetic IPSS were favorable (n=205), intermediate (n=104), unfavorable (n=86) and missing (n=10); 216 patients had IPSS Int-2 or High. One hundred and therty-three patients had progressed to a more advanced disease before allo-SCT. Prior to transplant, 77 patients had received AZA, either alone (AZA-alone-group; n=45) or AZA preceded or followed by intensive CT (AZA-chemo-group; n=32), generally due to failure of the first treatment given. The 328 remaining patients received BSC (n=162) or intensive CT (n=166) (no-AZA-group). In AZA groups, the drug was started 38 to 941 days after diagnosis (median 150) and discontinued 6 to 438 days before transplant (median 60) with a median number of 4 cycles (range 1–26). Overall, 178 patients (45%) were considered responders at transplant (in CR or PR), including 32/45 (71%) treated with AZA-alone, 19/32 (60%) with AZA-chemo, 6/162 (4%) with BSC and 121/166 (73%) with intensive CT, while 222 were transplanted with progressive disease (untreated, stable without hematological improvement, relapsed or refractory disease). Median age at allo SCT was 54 (range18–70). Patients received myeloablative (n=145) or nonmyeloablative (NMA) (n=260) conditioning with bone marrow (n=118) or PBSC (n=287) as source of stem cells. Compared with other treatment groups, patients belonging to AZA-alone-group were older (p =.025) and had more often Int-2 and high IPSS (p=.013) and poor cytogenetic IPSS (p 〈 .001) and received more often NMA conditioning (p =.005) from an unrelated donor (p=.007). As of April 1st, 2011, median FU was 4.6 years (range, 0.2–12.2). The estimated 3-year OS was 60%, 28%, 52% and 49% in the AZA-alone, AZA-chemo, BSC and intensive CT groups, respectively (p=.033); The estimated 3-year TRM was 13%, 29%, 34% and 20% in the AZA-alone, AZA-chemo, BSC and intensive CT groups, respectively (p=.055) and 3-year relapse was 31%, 41%, 29% and 38% in the AZA-alone, AZA-chemo, BSC and intensive CT groups respectively (p=.169). Multivariate analyses confirmed the influence of prior treatment with an unfavorable outcome in patients of the AZA-chemo group (who received CT before or after AZA) on OS and EFS (p=.003 and p=.0013, respectively), in spite of the fact that, 60% of the patients in that group had achieved at least PR at transplant. Conclusion: With the goal of down-staging underlying disease before allo-SCT, AZA treatment appears to be a valid therapeutic approach, but mainly in patients receiving AZA alone since allo-SCT in patients who required both AZA and chemotherapy had less satisfactory outcomes, possibly reflecting additional toxicity and/or more resistant disease. Disclosures: Michallet: Celgen: Honoraria. Mohty:celgene: Honoraria. Fenaux:Celgene: Honoraria, Research Funding. Yakoub-Agha:celgene: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.160.160
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 9
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    Clinical relevance of recipient leukocyte infusion as antitumor therapy following nonmyeloablative allogeneic hematopoietic cell transplantation
    Elsevier BV ; 2006
    In:  Experimental Hematology Vol. 34, No. 9 ( 2006-09), p. 1270-1276
    Details
    In: Experimental Hematology, Elsevier BV, Vol. 34, No. 9 ( 2006-09), p. 1270-1276
    Type of Medium: Online Resource
    ISSN: 0301-472X
    URL: Article
    DOI: 10.1016/j.exphem.2006.04.022
    RVK:
    XA 42470
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2006
    detail.hit.zdb_id: 185107-X
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  • 10
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    Association Between Multiple Mismatches at the HLA-DPB1 and DRB3/4/5 Genes and Adverse Outcomes in HLA-a, -B, -C, -DRB1 and -DQB1 Identical Hematopoietic Stem Cell Transplantation: A Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC) and the Francophone Society for Histocompatibility and Immunogenetics (SFHI)
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 4660-4660
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4660-4660
    Abstract: Background: Matching for all alleles of the HLA-A, -B, -C, and -DRB1 loci (8/8 match) is associated with the highest overall survival (OS) rates after unrelated donor (URD) hematopoietic stem cell transplantation (HSCT). In Europe, patients (pts) are also matched at the HLA-DQB1 loci (10/10 match) with no overall evidence of improved OS. HLA-DPB1 mismatching has been associated with a higher risk of acute graft-versus-host disease (aGvHD) and a decreased risk of relapse. A detrimental role of additional HLA-DQB1, HLA-DPB1 and HLA-DRB3/4/5 mismatches (MM) has been recently identified on OS but only in 7/8 HLA-A, -B, -C, and -DRB1 loci URDs HSCT. We investigated the impact of HLA-DPB1 and HLA-DRB3/4/5 MM on outcomes in a large cohort of 10/10 matched URD HSCTs. Patients and methods: 2,393 pts who received an initial HSCT from a 10/10 matched URD in 35 French centers were included between January 2000 and October 2012. Informed consent was obtained in accordance with the Declaration of Helsinki. High-resolution typing was performed for HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 and -DRB3/4/5 loci for all donor/recipient pairs. Clinical data were obtained through ProMISe (Project Manager Internet Server), an internet-based system shared by all French transplantation centers. Impact of HLA-DRB3/4/5 and -DPB1 MM was quantitatively and qualitatively evaluated. For quantitative evaluation, patients were classified into 5 different groups according to their global matching level for the 7 considered loci (14/14, 13/14, 12/14, 11/14, 10/14). For qualitative evaluation, MM type and directionality (GvH and host versus graft (HvG) directions) were evaluated. HLA-DPB1 MM were classified as permissive or non-permissive (K Fleischhauer, Lancet Oncol. 2012). The primary composite endpoint for the analysis was GvHD-free and relapse-free survival (GRFS). We defined early GRFS as being alive at 3 months after HSCT with no previous grade III-IV aGvHD and no relapse and late GRFS as being alive 〉 3 months with no previous grade III-IV aGvH, no relapse and no moderate or severe chronic GvHD (cGvHD). Late GRFS was evaluated at months 6, 12, 24 and 36 after HSCT. Acute GvHD, cGvHD, relapse and OS were also studied. Models were adjusted for HSCT period, disease risk, age, sex matching, stem cell source, and conditioning regimen. Results: Table 1showspopulation characteristics and distribution of cumulative MM. The median follow-up was 59 months. Compared to 14/14 pairs, quantitative evaluation showed a significantly lower early GRFS for pts who received a 10-11/14 (Hazard Ratio HR 2.0, 95% CI 1.4 to 2.9, p=0.0003) or a 12/14 URD HSCT (HR 1.4, 95% CI 1.1 to 1.8, p=0.01). This was related to a significantly increased risk of grade III-IV aGVHD associated with 10-11/14 (HR 2.3, 95% CI 1.5 to 3.7, p=0.0004) and 12/14 pairs (HR 1.7, 95% CI 1.2 to 2.4, p=0.003). 10-11/14 pairs were also associated with a higher risk of death at 3 months (HR 2, 95% CI 1.1 to 3.6, p=0.024). Qualitatively, in pts matched for HLA-DRB3/4/5 but MM for HLA-DPB1 (n=1846, 77.1%), 2 HLA-DPB1 MM and non-permissive HLA-DPB1 MM were associated with a lower early GRFS (HR 1.4, 95% CI 1.1 to 1.9, p=0.01 and HR 1.3, 95% CI 1.0 to 1.7, p=0.02 respectively) due to an increased risk of aGvHD (HR 1.7, 95% CI 1.2 to 2.5, p=0.002 and HR 1.50, 95% CI 1.08 to 2.08, p= 0.017 respectively). Outcomes were not influenced by either GvHD or HvG mismatch directions. Late GRFS analyses once adjusted were not significantly different according to MM numbers, type and directions. Only 19 pairs (0.8%) were DPB1 matched and DRB3/4/5 mismatched (high linkage disequilibrium between DRB3/4/5 and DRB1); HLA-DRB3/4/5 MM could thus not be qualitatively analyzed. Conclusion: MultipleHLA-DPB1 and HLA-DRB3/4/5 MM have an early impact after 10/10 matched URDs HSCT. The best outcomes are seen in 13 and 14/14 pairs. Early GRFS is significantly impacted by 10-11/14, 12/14, 2 DPB1 MM as well as non-permissive HLA-DPB1 MM URD HSCT which is related to an increased risk of grade III-IV aGvHD. There is a significantly increased risk of mortality for 10-11/14 pairs at 3 months. Prospective evaluation of matching for HLA-DPB1 and HLA-DRB3/4/5 is warranted to reduce early post-HSCT toxicity in donor-recipient 10/10 matched pairs. Disclosures Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Peffault De Latour:Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.4660.4660
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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